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Abstract: A general protocol for the design of successful chiral derivatizing agents (CDAs) for the NMR assignment of absolute configuration is described. The design of the most efficient arylalkoxyacetic acid reagent for the assignment of chiral thiols is taken as example. The importance of theoretical calculations in the discovery of the conformational preference of modelled arylmethoxyacetic acid (AMAA) thioesters is stressed, as well as NMR experiments to confirm the conformations predicted for the different CDAs and to select for synthesis the most adequate for that substrate. The modification of the aryl moiety of the AMAA system has shown not to provide especially good CDAs while the introduction of a sterically hindered tert-BuO group results in a more appropriate conformation leading to 2-naphtyl-tert-butoxyacetic acid (2-NTBA) as the most efficient CDA for thiols. [Copyright &y& Elsevier]

A general methodology for assigning the configuration of chiral mono- and polyfunctional compounds by NMR is presented. The approach is based on the use of polystyrene-bound chiral derivatizing agents (CDA-resins) specifically designed to achieve the high-yield formation of the covalent linkages (amide or ester bonds) between the substrate and the chiral auxiliary within the NMR tube, without the need for other manipulations, on a microscale level and in a short time. The deuterated NMR solvents (CDCl3, CD3CN, CS2/CD2Cl2) are also the reaction solvents and separations, purifications or workups of any kind are not necessary prior to recording the spectra. The CDA-resins prepared included MPA, 9-AMA, BPG, MTPA, and 2-NTBA as auxiliary agents incorporated either as single enantiomers or as mixed combinations of the (R)- and the (S)-enantiomers at unequal and known ratios. The high versatility of these systems was successfully demonstrated in a variety of ways based on double and single derivatization, low temperature experiments, or the formation of metal complexes. The approach allowed the absolute configurations of chiral primary amines, primary and secondary alcohols, cyanohydrins, thiols, diols, triols, and amino alcohols to be determined. Extensive high-resolution magic angle spinning (HR-MAS) NMR experiments allowed the characterization of the new CDA-resins and enabled the study of their stability and regioselectivity. [ABSTRACT FROM AUTHOR]